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Biomedical subjects

F M Muggia

Publications and source records attributed to F M Muggia.

At least 325 records · Page 18Linked to original sources
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Role of chemotherapy in head and neck cancer: systemic use of single agents and combinations in advanced disease.

Chemotherapy of head and neck cancer has recently been receiving increasing attention as a treatment modality. The basis for this interest has been the availability of at least three agents with reproducible antitumor activity: methotrexate, bleomycin, and cisplatinum (diamminedichloroplatinum). These agents alone or in combination have been demonstrated to be of palliative value in patients whose disease recurs or is too advanced for other therapeutic modalities. Although the multiple drug regimens used have not been curative, their relative effectiveness has raised hopes that, in combination with other modalities, they may lead to improvements in survival and in local control in earlier stages of disease. In addition, as a result of multimodality approaches, it is hoped that it may be possible to identify the role of chemotherapy and specific agents in the treatment of various sites of origin of these tumors. The interaction of chemotherapy and radiation--and the use of intraarterial chemotherapy--fall beyond the scope of this review but constitute another important aspect for investigation in the treatment of these malignancies.

Bleomycin↗
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Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies.

Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles.

Animals↗
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Sequential single agents as first-line chemotherapy for ovarian cancer: a strategy derived from the results of GOG-132.

First-line chemotherapy for ovarian cancer during the past decade has evolved toward the use of carboplatin and paclitaxel combinations. This has been based on randomized trials showing that combinations of these two drugs lead to a outcome similar to that obtained using cisplatin and paclitaxel (that had, in turn, proven superior in progression-free survival and overall survival to cisplatin and cyclophosphamide) but with less toxicity. Surprisingly, taxane-platinum combinations were not superior to control arms in two studies (ICON3 and GOG-132) utilizing carboplatin or cisplatin as the comparators. This has renewed interest in the role of single agents in first-line chemotherapy - a concept also supported by a number of prior clinical trials with single-agent platinum compounds yielding results not inferior to combinations. Early 'pre-emptive' crossover (prior to the stipulated clinical progression) to paclitaxel or a paclitaxel-containing regimen, however, occurred in 24% of patients initially treated with cisplatin on GOG-132. This has led to the interpretation of this trial as a combination versus sequential design. Although not subscribing to this interpretation, the results of GOG-132 and ICON3 not only raise doubts over a clear superiority of combinations over single agents but also lead to a consideration of sequential treatment designs for first line. Advantages of such designs are: (a) ability to provide 'dose-dense' platinums followed by 'dose-dense' paclitaxel and, perhaps, other drugs; and (b) the potential of acquiring biological data linked to the antitumor effects of a specific drug. Mathematical modeling and recent positive results in breast cancer adjuvant therapy support the use of 'dose-dense' strategies, and these should be considered in the design of future trials in ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
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BRCA1 germline mutation presenting as an adenocarcinoma of unknown primary.

BACKGROUND: The work-up of adenocarcinoma of unknown primary usually includes history, physical examination, radiographic imaging, tumor markers, and more recently molecular and genetic information. We report here on how the suggestion by family history of a BRCA1 mutation guided the diagnostic and therapeutic approach in a patient with metastatic carcinoma of unknown primary. METHODS: BRCA1 mutation was screened for by polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis. Primers for PCR amplification included selected BRCA1 exons 2, 110, 11L, 13, and 20. The PCR product was cloned into a PCRII vector and sequenced with a Sequenase Version 2.0 Sequencing Kit. RESULTS: Single-strand conformational polymorphism analysis suggested a mutation in the region of exon 20 and sequencing confirmed the presence of a germline mutation 5382insC. CONCLUSIONS: This case illustrates an unusual presentation of adenocarcinoma of unknown primary in a patient with a germline BRCA1 mutation, the use of a suspected germline mutation to guide the work-up and treatment, and finally the value of positron emission tomography scanning in the work-up of an unknown primary.

Adenocarcinoma↗
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High dose intensity of cisplatin and etoposide in adenocarcinoma of unknown primary.

Adenocarcinoma of unknown primary (AUP) has generally a poor prognosis. Previous studies have suggested that Cisplatin and Etoposide have activity in AUP. The aim of this study was to determine if dose intensification of this combination would result in increased efficacy. Each 28 day cycle consisted of Cisplatin 100 mg/m2 given on Day 1 and 8 with Etoposide 80 mg/m2 given on day 1, 2, 8 and 9. Sixteen patients (Pts) with no prior chemotherapy were accrued to this study. Predominant sites of disease were lung, liver, and bone. BHCG and AFP were not elevated. One complete remission was seen in a patient with a mediastinal mass (duration of remission = 59 weeks). Two other patients had a partial response. Overall response rate was 19%. Moderate to severe renal toxicity was recorded in 8 patients, with neuro- and ototoxicities in 2 patients each. Severe granulocytopenia occurred in 8 patients, and one patient died of congestive heart failure on day 1 of cycle 2. This excessive toxicity, without enhanced efficacy does not encourage a more extensive empiric trial by this dose schedule in the treatment of AUP.

Adenocarcinoma↗
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A new look at radionuclides therapy in metastatic disease of bone (review and prospects).

Bone-seeking radionuclides have been used to treat bone pain due to metastatic bone disease for over 40 years. More than 10 clinical studies using radiostrontium (Sr-89) have shown benefit in about 70-80% of patients having refractory bone pain from prostate, breast and other metastatic bone cancers, with minimal hematological toxicity. Other radionuclides, such as, radiophosphate (P-32), Yttrium-90, lodine-131, Rhenium-186, have also been used. Tumor necrosis has been found within the range of beta irradiation from the surrounding shell of bone incorporating the radionuclide. New strategies using radionuclides may be able to provide more effective methods of treatment, perhaps, beyond palliation. For example, the effect of low dose continuous radiation can be potentiated by hypoxic cell sensitizers. In addition, the kinetics of radionuclide uptake and retention can be modulated to increase the dose of radiation delivered to osteoblastic metastatic lesions, such as osteosarcoma.

Bone Neoplasms↗
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A quick method for concentrating and processing cancer cells from serous fluids and fine-needle nodule aspirates.

A quick method of concentrating cancer cells and the preparation of cytological slides from body fluids and aspirates is described, using a single Ficoll gradient and cytocentrifuge. The method eliminates the disadvantages of conventional techniques, i.e., excess contamination by red (erythrocytes) or white (leukocytes) blood cells and a scarcity of cancer cells. Because the technique is simple and requires only standard cytotechnological equipment, it can be easily adopted as an aid to diagnostic routine in cancer cytology.

Ascitic Fluid↗
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Characterization of conditions in which dipyridamole enhances methotrexate toxicity in L1210 cells.

In vitro studies in exponentially growing L1210 cells utilizing DNA flow cytometry and cell proliferation measurements indicate enhancement of methotrexate effects by Dipyridamole provided: Methotrexate concentrations exceed those required to shut off maximally de novo pathways of purine and pyrimidine synthesis (i.e. 30 nM for 48 h), and Dipyridamole concentrations exceed 3 microM. In 10% fetal calf serum, this concentration inhibits tritiated thymidine uptake by about 80%. These data should prove helpful in the planning of clinical studies with dipyridamole or other inhibitors of nucleoside transport used to potentiate inhibitors of de novo pathways.

Animals↗
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Toxic effects of cis-dichlorodiammineplatinum(II) in man.

Administration of cis-dichlorodiammineplatinum(II) may be associated with a number of serious side effects, including nephrotoxicity, gastroeintestinal side effects (nausea, vomiting, and diarrhea), myelosuppression, and occasional transient elevations in liver function tests. In addition, ototoxicity (tinnitus and hearing loss), anaphylactic reactions, peripheral neuropathies, and hypomagnesemia with resulting tetany may also be encountered. The toxic potential of this new agent necessitates careful clinical monitoring during treatment.

Anemia↗
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Analysis and interpretation of response rates for anticancer drugs.

A statistical method for interpreting data on the efficacy of anticancer agents is proposed. Tables were prepared for the retrospective analysis of studies evaluating the activity of anticancer agents against individual tumor types. The number of responding patients and the number of patients entered in the study were used to more objectively and formally determine the future disposition of the drug. Several examples of clinical studies show that use of our tables allows a more satisfactory and reliable classification than is often currently reported.

Antineoplastic Agents↗
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The delta and epsilon errors in the assessment of cancer clinical trials.

The error probabilities alpha and beta are widely used to compute sample sizes and to analyze results of clinical trials. These errors are, however, not the only probabilities to consider when assessing results of clinical studies. The rate of false positive (delta) and false negative (epsilon) results allows one to determine if an experimental finding is likely to reflect the true situation in the population of interest. The delta error is generally high in randomized phase III and in early phase II clinical trials in cancer patients, whereas the epsilon error is relatively low in these settings. This is essentially due to the small probability of detecting a more effective treatment or a new chemotherapeutic agent active in cancer. The delta error could be considerably reduced by increasing the sample sizes and by restricting the allowance made for the alpha error, which should be set at a 1% level as a minimum requirement.

Antineoplastic Agents↗